1. Field of the Invention
The invention relates generally to a method and apparatus of noninvasive glucose concentration estimation. More particularly, the invention relates to a method of adapting in-vitro models to aid in noninvasive glucose determination.
2. Description of Related Art
Spectroscopy-based noninvasive analyzers deliver external energy in the form of light to a specific sample site, region, or volume of the human body, wherein the photons interact with a tissue sample, thus probing chemical and physical features. A portion of the incident photons are specularly reflected, diffusely reflected, scattered, or transmitted out of the body and are subsequently detected. Based upon knowledge of the incident photons and the detected photons, the chemical and/or structural basis of the sampled site is deduced. A distinct advantage of a noninvasive analyzer is the ability to analyze chemical and structural constituents in the body in a pain-free manner while limiting both consumables and possible generation of biohazards. Additionally, noninvasive analyzers allow multiple analytes or structural features to be determined at one time. Common examples of noninvasive analyzers are those using magnetic resonance imaging (MRI) or x-rays, pulse oximeters, and noninvasive glucose concentration analyzers. With the exception of x-rays, these determinations are performed using relatively harmless wavelengths of radiation. Examples described herein focus on noninvasive glucose concentration estimation, but the principles apply to other noninvasive measurements and/or determination of additional blood or tissue analytes.
Diabetes
Diabetes is a chronic disease that results in abnormal production and use of insulin, a hormone that facilitates glucose uptake into cells. While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity play roles. Diabetics have an increased health risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics often have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide. Moreover, diabetes is merely one among a group of disorders of glucose metabolism that also includes impaired glucose tolerance and hyperinsulinemia, which is also known as hypoglycemia.
Diabetes Prevalence and Trends
The prevalence of individuals with diabetes is increasing with time. The World Health Organization (WHO) estimates that diabetes currently afflicts 154 million people worldwide. There are 54 million people with diabetes living in developed countries. The WHO estimates that the number of people with diabetes will grow to 300 million by the year 2025. In the United States, 15.7 million people or 5.9 percent of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by 6% in 1999 and rose by 33% between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy alone exceeds $90 billion per year. [Diabetes Statistics, National Institutes of Health, Publication No. 98-3926, Bethesda, Md. (November 1997)].
Long-term clinical studies demonstrate that the onset of diabetes related complications is significantly reduced through proper control of blood glucose concentrations. See, for example, The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N. Eng. J. of Med., 329:977-86 (1993); U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837-853 (1998); and Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichizi, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study, Diabetes Res. Clin. Pract., 28:13-117 (1995).
A vital element of diabetes management is the self-monitoring of blood glucose concentration by diabetics in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood or interstitial fluid through the skin prior to analysis, (The Diabetes Control and Complication Trial Research Group, supra). As a result, noninvasive measurement of glucose concentration is identified as a beneficial development for the management of diabetes. Implantable glucose concentration analyzers coupled to an insulin delivery system providing an artificial pancreas are also being pursued.
Noninvasive Glucose Concentration Determination
There exist a number of noninvasive approaches for glucose concentration determination. These approaches vary widely, but have at least two common steps. First, an apparatus is used to acquire a reading from the body without obtaining a biological sample. Second, an algorithm converts this reading into a glucose concentration estimation.
One species of noninvasive glucose concentration analyzers includes those based upon the collection and analysis of spectra. Typically, a noninvasive apparatus uses some form of spectroscopy to acquire the signal or spectrum from the body. Spectroscopic techniques include but are not limited to Raman and fluorescence, as well as techniques using light from ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-infrared (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein. See, for example, K. Hazen Glucose determination in biological matrices using near-infrared spectroscopy, doctoral dissertation, University of Iowa, (1995). It is important to note, that these techniques are distinct from the traditional invasive and alternative invasive techniques listed above in that the sample analyzed is a portion of the human body in-situ, not a biological sample acquired from the human body.
Typically, three modes are used to collect noninvasive scans: transmittance, transflectance, and/or diffuse reflectance. For example the light, spectrum, or signal collected is light transmitted through a region of the body, diffusely transmitted, diffusely reflected, or transflected. Transflected refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point or region of the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region. When using the near-infrared to sample skin tissue, the transflected radiation typically radially disperses 0.2 to 5 mm or more away from the incident photons depending on the wavelength used. For example, light that is strongly absorbed by the body, such as light near the water absorbance maxima at 1450 or 1950 nm, is collected after a small radial divergence in order to be detected and light that is less absorbed, such as light near water absorbance minima at 1300, 1600, or 2250 nm is, optionally, collected at greater radial or transflected distances from the incident photons.
Noninvasive techniques are used to analyze tissue and/or blood. Regions or volumes of the body subjected to noninvasive measurements include: a hand, finger, fingertip, palmar region, base of thumb, forearm, volar aspect of the forearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye, tongue, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toe. Notably, noninvasive techniques are not necessarily based upon spectroscopy. For example, a bioimpedence meter is a noninvasive device. In this document, any device that reads or determines a glucose concentration from the body without penetrating the skin and collecting a biological sample is referred to as a noninvasive glucose concentration analyzer. Some noninvasive analyzers use invasive methods for purposes of calibration or bias correction of estimated glucose concentration values.
Calibration
Optical based glucose concentration analyzers require calibration. This is true for all types of glucose concentration analyzers, such as traditional invasive, alternative invasive, noninvasive, and implantable analyzers. A fundamental feature of noninvasive glucose concentration analyzers is that they are secondary in nature, that is, they do not measure blood glucose concentrations directly. Therefore, a primary method is required to calibrate these devices to measure blood glucose concentrations properly. Many methods of calibration exist.
One noninvasive technology, near-infrared spectroscopy, requires that a mathematical relationship between an in-vivo near-infrared spectrum and the actual blood glucose concentration is developed. This relationship is achieved through the collection of in-vivo near-infrared measurements with corresponding blood glucose concentrations that are obtained directly through the use of measurement tools, such as a traditional invasive or alternative invasive reference device.
For spectrophotometric based analyzers, there are several univariate and multivariate methods that are used to develop the mathematical relationship between the measured signal and the actual blood glucose concentration. However, the basic equation being solved is known as the Beer-Lambert Law. This approximation states that the strength of an absorbance/reflectance measurement is proportional to the concentration of the analyte which is being measured, as in equation 1,A=εbC  (1)where A is the absorbance/reflectance measurement at a given wavelength of light, ε is the molar absorptivity associated with the molecule of interest at the same given wavelength, b is the distance that the light travels, and C is the concentration of the molecule of interest (glucose).
Chemometric calibration techniques extract a glucose or glucose-related signal from acquired spectra through various methods of signal processing and calibration including one or more mathematical models. The models are developed through the process of calibration on the basis of an exemplary set of spectral measurements known as the calibration set and an associated set of reference blood glucose concentrations based upon an analysis of capillary blood or venous blood. Common multivariate approaches, requiring an exemplary reference glucose concentration for each sample spectrum in a calibration, include partial least squares (PLS) and principal component regression (PCR). Many additional forms of calibration are known to those skilled in the art.
There are a number of reports of noninvasive glucose technologies. Some of these relate to general instrumentation configurations required for noninvasive glucose concentration determination while others refer to sampling technologies. Those related to the present invention are briefly reviewed here:
General Instrumentation
Pulse oximeters operate on wavelengths about 660 and 805 nm, which correlate oxy-hemoglobin and deoxy-hemoglobin absorbance bands. Siemens, A G, Verfahren und Gerät zur kolorimetrischen Untersuchung von Substanzen auf signifikante bestandteile (Method and device for a calorimetric examination of substances for significant components), DE 2,255,300, filed Nov. 11, 1972 describes a pulse oximeter meter operating in a spectral region of 600 to 900 nm, which is at shorter wavelengths than the noninvasive glucose concentration meters of this invention that operate from about 1100 to 2500 nm or ranges therein.
K. Schlager, Non-invasive near infrared measurement of blood analyte concentrations, U.S. Pat. No. 4,882,492 (Nov. 21, 1989) describes a dual beam noninvasive glucose analyzer. This patent is commonly owned with the current application.
R. Barnes, J. Brasch, D. Purdy, W. Lougheed, Non-invasive determination of analyte concentration in body of mammals, U.S. Pat. No. 5,379,764 (Jan. 10, 1995) describe a noninvasive glucose concentration determination analyzer that uses data pretreatment in conjunction with a multivariate analysis to determine blood glucose concentrations.
P. Rolfe, Investigating substances in a patient's bloodstream, UK Patent Application Ser. No. 2,033,575 (Aug. 24, 1979) describes an apparatus for directing light into the body, detecting attenuated backscattered light, and using the collected signal to determine glucose concentrations in or near the bloodstream.
C. Dahne, D. Gross, Spectrophotometric method and apparatus for the non-invasive, U.S. Pat. No. 4,655,225 (Apr. 7, 1987) describe a method and apparatus for directing light into a patient's body, collecting transmitted or backscattered light, and determining glucose concentrations from selected near-infrared (near-IR) wavelength bands. Wavelengths include 1560 to 1590, 1750 to 1780, 2085 to 2115, and 2255 to 2285 nm, with at least one additional reference signal from 1000 to 2700 nm.
M. Robinson, K. Ward, R. Eaton, D. Haaland, Method and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids, U.S. Pat. No. 4,975,581 (Dec. 4, 1990) describe a method and apparatus for measuring a concentration of a biological analyte, such as glucose using infrared spectroscopy in conjunction with a multivariate model. The multivariate model is constructed from a plurality of known biological fluid samples.
J. Hall, T. Cadell, Method and device for measuring concentration levels of blood constituents non-invasively, U.S. Pat. No. 5,361,758 (Nov. 8, 1994) describe a noninvasive device and method for determining analyte concentrations within a living subject using polychromatic light, a wavelength separation device, and an array detector. The apparatus uses a receptor shaped to accept a fingertip with means for blocking extraneous light.
S. Malin, G Khalil, Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy, U.S. Pat. No. 6,040,578 (Mar. 21, 2000) describe a method and apparatus for determination of an organic blood analyte using multi-spectral analysis in the near-infrared. A plurality of distinct nonoverlapping spectral regions of wavelengths is incident upon a sample surface, diffusely reflected radiation is collected, and the analyte concentration is determined via chemometric techniques. This patent is commonly owned with the current application.
J. Garside, S. Monfre, B. Elliott, T. Ruchti, G. Kees, Fiber optic illumination and detection patterns, shapes, and locations for use in spectroscopic analysis, U.S. Pat. No. 6,411,373 (Jun. 25, 2002) describe the use of fiber optics for use as excitation and/or collection optics with various spatial distributions. This patent is commonly owned with the current application.
Specular Reflectance
R. Messerschmidt, D. Sting Blocker device for eliminating specular reflectance from a diffuse reflectance spectrum, U.S. Pat. No. 4,661,706 (Apr. 28, 1987) describe a reduction of specular reflectance by a mechanical device. A blade-like device skims the specular light before it impinges on the detector. This system leaves alignment concerns and improvement in efficiency of collecting diffusely reflected light is needed.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,636,633 (Jun. 10, 1997) describe a specular control device for diffuse reflectance spectroscopy using a group of reflecting and open sections.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,935,062 (Aug. 10, 1999) and R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 6,230,034 (May 8, 2001) describe a diffuse reflectance control device that discriminates between diffusely reflected light that is reflected from selected depths. This control device additionally acts as a blocker to prevent specularly reflected light from reaching the detector.
Malin, supra, describes the use of specularly-reflected light in regions of high water absorbance, such as 1450 and 1900 nm, to mark the presence of outlier spectra wherein the specularly reflected light is not sufficiently reduced. This patent is commonly owned with the current application.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. Pat. No. 6,534,012 (Mar. 18, 2003) describe a mechanical device for applying sufficient and reproducible contact of the apparatus to the sample medium to minimize specular reflectance. Further, the apparatus allows for reproducible applied pressure to the sample site and reproducible temperature at the sample site. This patent is commonly owned with the current application.
Sample Preparation
B. Wenzel, S. Monfre, T. Ruchti, K. Meissner, F. Grochocki, T. Blank, J. Rennert, A method for quantification of stratum corneum hydration using diffuse reflectance spectroscopy, U.S. Pat. No. 6,442,408 (Aug. 27, 2002) describe a method and apparatus for determination of tissue variability, such as water content of the epidermal ridge and penetration depth of incident light. This patent is commonly owned with the current application.
Temperature
K. Hazen, Glucose determination in biological matrices using near-Infrared spectroscopy, doctoral dissertation, University of Iowa (1995) describes the adverse effect of temperature on near-infrared based glucose concentration estimations. Physiological constituents have near-infrared absorbance spectra that are sensitive, in terms of magnitude and location, to localized temperature and the sensitivity impacts noninvasive glucose concentration estimation.
Coupling Fluid
A number of sources describe coupling fluids as a consideration in an optical sampling method or apparatus.
Index of refraction matching between the sampling apparatus and sampled medium is well known. Glycerol is commonly used to match refractive indices of optics and skin.
R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,655,530 (Aug. 12, 1997), and R. Messerschmidt Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,823,951 describe an index-matching medium for use between a sensor probe and the skin surface. The index-matching medium is a composition containing perfluorocarbons and chlorofluorocarbons.
M. Robinson, R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 6,152,876 (Nov. 28, 2000) and M. Rohrscheib, C. Gardner, M. Robinson, Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration, U.S. Pat. No. 6,240,306 (May 29, 2001) describe an index-matching medium to improve the interface between the sensor probe and skin surface during spectroscopic analysis. The index-matching medium is preferably a composition containing chlorofluorocarbons with optional perfluorocarbons.
T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe guide placement guide, U.S. Pat. No. 6,415,167 (Jul. 2, 2002) describe a coupling fluid of one or more perfluoro compounds where a quantity of the coupling fluid is placed at an interface of the optical probe and measurement site. Advantageously, perfluoro compounds lack the toxicity associated with chlorofluorocarbons. This patent is commonly owned with the current application.
Positioning
T. Blank, supra, describes the use of a guide in conjunction with a noninvasive glucose concentration analyzer in order to increase precision of the location of the sampled tissue site resulting in increased accuracy and precision in noninvasive glucose concentration estimations. This patent is commonly owned with the current application.
J. Griffith, P. Cooper, T. Barker, Method and apparatus for non-invasive blood glucose sensing, U.S. Pat. No. 6,088,605 (Jul. 11, 2000) describe an analyzer with a patient forearm interface in which the forearm of the patient is moved in an incremental manner along the longitudinal axis of the patient's forearm. Spectra collected at incremental distances are averaged to take into account variations in the biological components of the skin. Between measurements rollers are used to raise the arm, move the arm relative to the apparatus and lower the arm by disengaging a solenoid causing the skin lifting mechanism to lower the arm into a new contact with the sensor head. The Griffith teachings do not suggest the use of a controlled pressure between the forearm sample site and the sampling head. In addition, spectra are not collected during a period of relative motion between the sample and the analyzer.
Pressure
E. Chan, B. Sorg, D. Protsenko, M. O'Neil, M. Motamedi, A. Welch, Effects of compression on soft tissue optical properties, IEEE Journal of Selected Topics in Quantum Electronics, Vol. 2, no. 4, 943-950 (1996) describe the effect of pressure on absorption and reduced scattering coefficients from 400 to 1800 nm. Most specimens show an increase in the scattering coefficient with compression.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. Pat. No. 6,534,012 (Mar. 18, 2003) describe in a first embodiment a noninvasive glucose concentration estimation apparatus for either varying the pressure applied to a sample site or maintaining a constant pressure on a sample site in a controlled and reproducible manner by moving a sample probe along the z-axis perpendicular to the sample site surface. In an additional described embodiment, the arm sample site platform is moved along the z-axis that is perpendicular to the plane defined by the sample surface by raising or lowering the sample holder platform relative to the analyzer probe tip. The U.S. Pat. No. 6,534,012 further teaches proper contact between the probe tip and the sample site to be that point at which specularly-reflected light is substantially zero at the water bands at 1950 and 2500 nm. This patent is commonly owned with the current application.
M. Makarewicz, M. Mattu, T. Blank, G. Acosta, E. Handy, W. Hay, T. Stippick, B. Richie, Method and apparatus for minimizing spectral interference due to within and between sample variations during in-situ spectral sampling of tissue, U.S. patent application Ser. No. 09/954,856 (filed Sep. 17, 2001) describe a temperature and pressure controlled sample interface. The means of pressure control is a set of supports for the sample that control the natural position of the sample probe relative to the sample. This patent is commonly owned with the current application.
Data Processing
R. Barnes, J. Brasch, Non-invasive determination of glucose concentration in body of patients, U.S. Pat. No. 5,070,874 (Dec. 10, 1991) describe a method of collecting near-infrared noninvasive spectra, preprocessing with an nthderivative, and determining a glucose concentration from the resulting spectrum.
Several approaches exist that employ diverse preprocessing methods to remove spectral variation related to the sample and instrumental variation including normalization, smoothing, derivatives, multiplicative signal correction, [P. Geladi, D. McDougall, H. Martens Linearization and scatter-correction for near-infrared reflectance spectra of meat, Applied Spectroscopy, vol. 39, 491-500 (1985)], standard normal variate transformation, [R. Barnes, M. Dhanoa, S. Lister, Applied Spectroscopy, 43, 772-777 (1989)], piecewise multiplicative scatter correction, [T. Isaksson and B. Kowalski, Applied Spectroscopy, 47, 702-709 (1993)], extended multiplicative signal correction, [H. Martens, E. Stark, J. Pharm Biomed Anal, 9, 625-635 (1991)], pathlength correction with chemical modeling and optimized scaling, [GlucoWatch automatic glucose biographer and autosensors, Cygnus Inc., Document #1992-00 (Rev. March 2001)], and finite impulse response filtering, [S. Sum, Spectral signal correction for multivariate calibration, Doctoral Dissertation, University of Delaware (1998); S. Sum, and S. Brown, Standardization of fiber-optic probes for near-infrared multivariate Calibrations, Applied Spectroscopy, Vol. 52, No. 6, 869-877 (1998); and T. Blank, S. Sum, S. Brown, S. Monfre, Transfer of near-infrared multivariate calibrations without standards, Analytical Chemistry, 68, 2987-2995 (1996)].
In addition, a diversity of signal, data or pre-processing techniques are commonly reported with the fundamental goal of enhancing accessibility of the net analyte signal [D. Massart, B. Vandeginste, S. Deming, Y. Michotte, L. Kaufman, Chemometrics: a textbook, New York, Elsevier Science Publishing Company, Inc., 215-252 (1990); A. Oppenheim, R. Schafer, Digital Signal Processing, Englewood Cliffs, N.J.: Prentice Hall, 1975, 195-271; M. Otto, Chemometrics, Weinheim: Wiley-VCH, 51-78 (1999); K. Beebe, R. Pell, M. Seasholtz, Chemometrics A Practical Guide, New York: John Wiley & Sons, Inc., 26-55 (1998); M. Sharaf, D. Illman and B. Kowalski, Chemometrics, New York: John Wiley & Sons, Inc., 86-112 (1996); and A. Savitzky, M. Golay, Smoothing and differentiation of data by simplified least squares procedures, Anal. Chem., vol. 36, no. 8,1627-1639 (1964). A goal of these techniques is to attenuate the noise and instrument variation while maximizing the signal of interest.
While methods for preprocessing partially compensate for variation related to instrument and physical changes in the sample and enhance the net analyte signal in the presence of noise and interference, they are often inadequate for compensating for the sources of tissue-related variation. For example, the highly nonlinear effects related to sampling different tissue locations are not effectively compensated for through a pathlength correction because the sample is multi-layered and heterogeneous. In addition, fundamental assumptions inherent in these methods, such as the constancy of multiplicative and additive effects across the spectral range and homoscadasticity of noise are violated in the non-invasive tissue application.
Currently, no device using near-infrared spectroscopy for the noninvasive measurement of glucose has been approved for use by persons with diabetes due to technology limitations that include poor sensitivity, sampling problems, time lag, calibration bias, long-term reproducibility, stability, and instrument noise. Further, current reported versions of noninvasive glucose concentration analyzers do not consistently yield accurate estimations of glucose concentrations in long-term patient trials in the hands of a typical user or professional operator. Further limitations to commercialization include a poor form factor (large size, heavy weight, and no or poor portability) and usability. There exists, therefore, a long-felt need for a noninvasive approach to the estimation of glucose concentration that provides long-term accurate and precise glucose concentration estimations in a semi-continuous, continuous or semi-automated fashion. Development in this area is complicated by the very expensive in-vivo testing that is necessary on human subjects. Therefore, it is of great benefit to build a model, at least in part, using a set of in-vitro samples. The in-vitro samples are cheaper and are more readily controlled. This allows tight control of the experimental conditions, such as sampling, environmental conditions, pathlength, noise, and analyte and interference concentrations.